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| United States Patent |
5,192,752
|
|
Chapura
, et al.
|
*
March 9, 1993
|
Swallowable pharmaceutical compositions containing Colloidal Bismuth
Subcitrate
Abstract
Oral pharmaceutical compositions in unit dosage form suitable for
swallowing (especially capsules) comprising a safe and effective amount of
solid Colloidal Bismuth Subcitrate (CBS), and optionally one or more
pharmaceutically-acceptable carrier materials, wherein the packing density
of the dosage unit is less than about 1 g/ml.
| Inventors:
|
Chapura; Francis B. (Hamilton, OH);
Mitra; Sekhar (Cincinnati, OH)
|
| Assignee:
|
The Procter & Gamble Company (Cincinnati, OH)
|
| [*] Notice: |
The portion of the term of this patent subsequent to July 7, 2009
has been disclaimed. |
| Appl. No.:
|
640920 |
| Filed:
|
January 14, 1991 |
| Current U.S. Class: |
514/152; 514/192; 514/200; 514/398; 514/503 |
| Intern'l Class: |
A61K 031/65; A61K 031/43; A61K 031/545; A61K 031/415; A61K 031/29 |
| Field of Search: |
514/503,925,152,192,200,398
424/653
|
References Cited
U.S. Patent Documents
| 4801454 | Jan., 1989 | Conveney | 424/131.
|
| 4801608 | Jan., 1989 | Bos et al. | 514/925.
|
| 4940695 | Jul., 1990 | Conveney et al. | 514/925.
|
| 5008256 | Apr., 1991 | Clitherow | 514/184.
|
| 5013560 | May., 1991 | Stentz et al. | 424/653.
|
| Foreign Patent Documents |
| 206625 | Dec., 1986 | EP.
| |
| 206626 | Dec., 1986 | EP.
| |
| 206627 | Dec., 1986 | EP.
| |
| 282131 | Sep., 1988 | EP.
| |
| 282132 | Sep., 1988 | EP.
| |
| 437294 | Jul., 1991 | EP.
| |
| 1478742 | Jul., 1977 | GB.
| |
| 2220937 | Jan., 1990 | GB.
| |
| 86/05981 | Oct., 1986 | WO.
| |
Other References
Nwokolo et al. Aliment. Pharmacol. Therap., (1989), 3, pp. 21-28.
|
Primary Examiner: Waddell; Frederick E.
Assistant Examiner: Henley, III; Raymond J.
Attorney, Agent or Firm: Zerby; Kim William, Mohl; Douglas C., Witte; Richard C.
Claims
What is claimed is:
1. An oral pharmaceutical composition in solid unit dosage form suitable
for swallowing comprising a safe and effective amount of solid colloidal
bismuth subcitrate and, optionally, pharmaceutically-acceptable carrier
materials, wherein the packing density of the pharmaceutical composition
is less than about 1 g/ml.
2. The oral pharmaceutical composition according to claim 1 wherein the
packing density is within the range of from about 0.05 g/ml to less than
about 1 g/ml.
3. The oral pharmaceutical composition according to claim 2 wherein each
dosage unit comprises from about 30 to about 600 mg of solid colloidal
bismuth subcitrate.
4. The oral pharmaceutical composition according to claim 1 further
comprising at least one auxiliary medicament.
5. The oral pharmaceutical composition according to claim 4 wherein the
auxiliary medicament comprises at least one antimicrobial medicament safe
and effective against Helicobacter pylori.
6. An oral pharmaceutical composition in solid unit dosage form suitable
for swallowing comprising:
(a) from about 1% to about 100% solid colloidal bismuth subcitrate; and
(b) from about 0% to about 99% pharmaceutically-acceptable carrier
materials;
and wherein the packing density of the pharmaceutical composition is less
than about 1 g/ml.
7. The oral pharmaceutical composition in solid unit dosage form according
to claim 6 comprising:
(a) from about 25% to about 99% solid colloidal bismuth subcitrate;
(b) from about 1% to about 75% pharmaceutically-acceptable carrier
materials;
and wherein the packing density of the pharmaceutical composition is within
the range of from about 0.25 g/ml to less than about 0.9 g/ml.
8. The oral pharmaceutical composition according to claim 7 in solid unit
dosage form of a capsule.
9. The oral pharmaceutical composition according to claim 6 further
comprising at least one antimicrobial medicament safe and effective
against Helicobacter pylori.
10. The oral pharmaceutical composition according to claim 9 comprising at
least one antimicrobial medicament safe and effective against Helicobacter
pylori selected from the group consisting of metronidazole, tinidazole,
penicillin, cephalosporin, tetracycline, chinolones, macrolides, and
mixtures thereof.
11. An oral pharmaceutical composition in solid unit dosage form of a
capsule suitable for swallowing comprising:
(a) from about 25% to about 99% solid colloidal bismuth subcitrate; and
(b) from about 1% to about 75% pharmaceutically-acceptable carrier
materials;
and wherein the pharmaceutical composition is filled into a capsule to a
packing density within the range of from about 0.5 g/ml to about 0.75
g/ml.
12. The oral pharmaceutical composition according to claim 11 wherein the
capsule container itself is made of material selected from the group
consisting of gelatin, modified starch and cellulose derivative, and
wherein further the capsule dosage unit has a packing density of less than
about one g/ml.
13. The oral pharmaceutical composition according to claim 11 further
comprising at least one antimicrobial medicament safe and effective
against Helicobacter pylori selected from the group consisting of
metronidazole, tinidazole, penicillin, cephalosporin, tetracycline,
chinolones, macrolides, and mixtures thereof.
14. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 1.
15. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 4.
16. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 5.
17. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 9.
18. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 10.
19. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 11.
20. A method for treating or preventing gastrointestinal disorders in
humans or lower animals, said method comprising orally administering by
swallowing to a human or lower animal in need of such treatment or
prevention a safe and effective amount of an oral pharmaceutical
composition according to claim 13.
21. A method for manufacturing unit dosage forms suitable for swallowing,
said method comprising the step of forming a unit dosage of a dry
composition comprising solid colloidal bismuth subcitrate having a packing
density of less than about 1 g/ml.
22. The method according to claim 21 wherein a dry particulate composition
comprising solid colloidal bismuth subcitrate is filled into a capsule to
a packing density of less than about 1 g/ml.
Description
BACKGROUND OF THE INVENTION
The present invention relates to low density oral pharmaceutical
compositions in unit dosage form suitable for swallowing comprising solid
Colloidal Bismuth Subcitrate.
Solid Colloidal Bismuth Subcitrate ("CBS"; Trademark De-Nol.RTM. of
Gist-brocades N.V.) is the product of European Patent 0,075,992,
corresponding to U.S. Pat. No. 4,801,608. It is also the active ingredient
of British Patent 1,478,742. According to these specifications, CBS can be
formulated into pharmaceutical compositions in solid dosage form for oral
administration, such as tablets and capsules. Up to now only the tablet
form (both chewable and swallowable tablets) has been realized and it is
marketed in many countries.
The currently used swallowable tablet form of CBS has already been given to
hundreds of thousands of patients and its clinical efficacy and safety are
firmly established. However, recently there have been reports of a
transient sharp peak of bismuth blood level in humans after the ingestion
of this CBS-containing swallowable tablet, t.sub.max around 30 minutes
(see C. U. Nwokolo et al, Aliment. Pharmacol. Therap., 3, 1989, 29-39).
Since the therapeutic action of CBS is believed to be localized in the
gastrointestinal tract, even a transient peak of bismuth blood level does
not appear to serve any useful purpose and it is therefore desirable to
minimize bismuth blood levels if possible.
It has been discovered that this currently used tablet form (having a
density greater than 1 g/ml), in vitro in liquid acidic medium, has a
tendency to sink to the bottom of the liquid and dissolve by first forming
liquid CBS solution rather than the desired insoluble bismuth precipitate.
By contrast, unit dosage forms (as according to the present invention)
which are less dense than the current tablet form and also less dense than
the acidic medium (approximately 1 g/ml) do not form this initial CBS
liquid but rather quickly forms the desired insoluble bismuth precipitate.
Interestingly, when these low density unit dosage forms are weighted to
the bottom of the test liquid, again the CBS initially liquifies.
A low packing density of oral dosage units as specified above is contrary
to the current tendency in the art of pharmaceutical production, which is
to concentrate the oral dosage units, e.g. by compressing the contents of
oral capsules to a high density (see Hard Capsules, Development and
Technology, Ed. K. Ridgway 1987, chapter 9, G. C. Cole, pp. 92-103).
That the low density unit dosage form of the present invention in fact
substantially reduces bismuth blood levels as predicted by these different
in vitro characteristics has been confirmed by in vivo testing. The oral
dosage units of the present invention, when compared to swallowable
tablets comprising the same formula and dosage of CBS but with a higher
density, were found to give not only a lower maximal blood plasma bismuth
level (C.sub.max), but also a lower blood plasma bismuth rise (AUC) and a
lower bismuth excretion in the urine. Therefore, systemic bismuth
absorption after ingestion of the dosage units of the present invention
has proved to be lower than after ingestion of the prior swallowable
tablets. This is contrary to what one might expect--that less dense and
thereby more dispersible material would lead to more rapid dissolution and
consequently to greater absorption than compressing to higher density the
same material.
Thus, the oral dosage units of the present invention surprisingly give peak
bismuth plasma levels and a total bismuth absorption which are lower than
that of the denser dosage units.
An object of the present invention therefore is to provide an oral dosage
unit suitable for swallowing comprising CBS in a therapeutically effective
amount which substantially reduces bismuth absorption and thereby the
above described peak in the bismuth blood levels.
This and other objects of the present invention will become readily
apparent from the detailed description which follows.
All percentages and ratios used herein are by weight, and all measurements
made at 25.degree. C., unless otherwise specified.
SUMMARY OF THE INVENTION
The present invention relates to oral pharmaceutical compositions in unit
dosage form suitable for swallowing comprising a safe and effective amount
of solid colloidal bismuth subcitrate and, optionally,
pharmaceutically-acceptable carrier materials, wherein the packing density
of the pharmaceutical composition is less than about 1 g/ml.
The present invention also relates to a method for manufacturing unit
dosage forms suitable for swallowing comprising solid colloidal bismuth
subcitrate. Said method comprises the step of forming a unit dosage of a
dry composition comprising solid colloidal bismuth subcitrate having a
packing density of less than about 1 g/ml. Preferred is the method wherein
a dry particulate composition comprising solid colloidal bismuth
subcitrate is filled into a capsule to a packing density of less than
about 1 g/ml.
The present invention further relates to methods for treating or preventing
gastrointestinal disorders in humans or lower animals. These methods
comprise orally administering by swallowing to a human or lower animal in
need of such treatment or prevention a safe and effective amount of an
oral pharmaceutical composition according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
(1) Oral Pharmaceutical Compositions
The oral pharmaceutical compositions of the present invention comprise
colloidal bismuth subcitrate ("CBS") in unit dosage forms suitable for
swallowing (e.g., tablets and, especially, capsules) wherein the packing
density of the composition is less than about 1 g/ml. Preferably, these
compositions comprise the CBS and a pharmaceutically-acceptable carrier
material(s).
The term "packing density," as used herein, means the weight of the drug
mixture (active CBS ingredient plus carrier materials) in grams divided by
the volume occupied by the dose form expressed in milliliters, and, in
case of a filled capsule form, excludes the volume and weight of the
capsule container. Thus, the packing density can be varied by varying the
types and amounts of excipients added to the CBS and especially by varying
the pressure used in compressing the units. Oral pharmaceutical
compositions herein have packing density of less than about 1 g/ml,
preferably within the range of from about 0.05 g/ml to less than about 1
g/ml, more preferably from about 0.25 g/ml to about 0.9 g/ml, and most
preferably from about 0.5 g/ml to about 0.75 g/ml.
The particular agents for use herein, as well as the levels and amounts
preferred therefor, are described in greater detail hereinafter.
(a) Colloidal Bismuth Subcitrate
Colloidal bismuth Subcitrate ("CBS") is described in The Merck Index, 11th
Edition (1989), item 1296 (incorporated herein by reference in its
entirety), to have the approximate molecular formula of K.sub.3
(NH.sub.4).sub.2 [Bi.sub.6 O.sub.3 (OH).sub.5 (C.sub.6 H.sub.5
O.sub.7).sub.4 ]. The preparation and use of CBS is described in detail in
U.S. Pat. No. 4,801,608, to Bos et al, issued Jan. 31, 1989; and Great
Britain patent specification 1,478,742, published Jul. 6, 1977 by
Gist-brocades, N.V., the disclosures of both these patents being
incorporated herein by reference in their entirety. The CBS used in the
compositions of the present invention (preferably including any optional
carrier materials) is preferably in the form of granules or powders,
having a preferred particle size of less than about 1.5 mm.
The oral pharmaceutical compositions herein comprise a safe and effective
amount of CBS, typically in the amount of from about 30 mg to about 600 mg
per dosage unit, and preferably from about 37.5 mg to about 300 mg per
dosage unit. As a percentage of the oral pharmaceutical compositions, CBS
typically comprises from about 1% to about 100%, and preferably from about
25% to about 99%, by weight of the composition.
(b) Pharmaceutically-Acceptable Carrier Materials
The oral pharmaceutical compositions herein may also optionally comprise
one or more pharmaceutically-acceptable carrier materials. The term
"pharmaceutically-acceptable carrier materials," as used herein, means one
or more compatible solid or liquid filler diluents or encapsulating
substances which are suitable for oral administration to a human or lower
animal. The term "compatible," as used herein, means that the components
of the oral pharmaceutical composition are capable of being commingled
with the CBS, and with each other, in a manner such that there is no
interaction which would substantially reduce the pharmaceutical efficacy
of the pharmaceutical composition under ordinary use situations by
swallowing the composition. Pharmaceutically-acceptable carrier materials
must, of course, be of sufficiently high purity and sufficiently low
toxicity to render them suitable for oral administration to the human or
lower animal being treated.
To the CBS may be added any of the pharmaceutically-acceptable carrier
materials known in the art, which are compatible with CBS, such as:
diluents, like lactose, starch, microcrystalline cellulose, sorbitol,
mannitol, dibasic calcium phosphate dihydrate, calcium sulfate dihydrate,
sucrose-based diluents and mixtures thereof;
binders, like acacia, cellulose derivatives, gelatin, glucose,
polyvinylpyrrollidone, starch, sucrose, sorbitol, tragacanth, sodium
alginate and mixtures thereof;
disintegrants, like microcrystalline cellulose and cellulose derivatives,
starch and its derivatives, alginic acid and its derivatives, ion-exchange
resins, cross-linked sodium carboxymethyl cellulose, sodium starch
glycolate, cross-linked polyvinylpyrrollidone and formaldehyde-caseine;
lubricants, antiadherents and glidants, like magnesium-, calcium- and
sodium stearates, stearic acid, hydrogenated castor oil, talc, water,
polyethylene glycol, sodium laryl sulfate, magnesium laryl sulfate and
silica.
Furthermore, the pharmaceutically-acceptable carrier materials may also
comprise one or more auxiliary medicaments, preferably those which are
intended to act in combination with it, such as non-steroidal
anti-inflammatory compounds, H.sub.2 -antagonists, cytoprotectants (e.g.,
sucralfate), and synthetic prostaglandins. In particular the dosage units
may contain antimicrobially effective medicaments such as antibiotics and
chemotherapeutic compounds, more in particular medicaments effective
against Campylobacter pylori (recently renamed Helicobacter pylori), such
as the antimicrobially effective imidazoles, in particular metronidazole
and tinidazole, penicillins, cephalosporins, tetracyclines, chinolones and
macrolides. The dosage of the optionally present auxiliary medicaments
will depend on the effectivity of the particular medicament used. Optional
auxiliary medicaments useful herein are described in detail in: European
Patent Application Publication No. 206,625, published Dec. 30, 1986, by
Marshall; and International Publication No. WO 86/05981, published Oct.
23, 1986, by Borody, the disclosures of both these publications being
incorporated herein by reference in their entirety.
The most preferred oral dosage units according to the invention are
capsules, although tablets having a low density as defined above are also
possible. The material of swallowable capsules according to the invention
may be any of those known in the art, such as gelatine, modified starches,
such as hydroxyalkyl starch, and cellulose derivatives, such as cellulose
ethers, e.g. methyl cellulose. Preferably, the capsule material and size
of the capsule are chosen such that the capsule unit dosage form filled
with the drug mixture has a density of less than about 1 g/ml. Gelatine
capsules can be soft and hard. The dosage units according to the invention
may be further coated in order to provide for controlled release.
The oral pharmaceutical compositions herein preferably comprise from about
3 mg to about 1000 mg, more preferably from about 20 mg to about 150 mg,
of pharmaceutically-acceptable carrier material per 100 mg of CBS. As a
percentage of the oral pharmaceutical compositions,
pharmaceutically-acceptable carrier materials comprise from about 0% to
about 99%, and preferably from about 1% to about 75%, by weight of the
composition.
The method of manufacturing unit dosage forms suitable for swallowing
comprising CBS, according to the present invention, preferably comprises
the step of forming a unit dosage of a dry composition comprising CBS
having a packing density of less than about 1 g/ml. Preferred is the
method wherein a dry particulate composition (e.g., granulate; powder)
comprising CBS is filled into a capsule to a packing density of less than
about 1 g/ml.
(2) Methods for Treating or Preventing Gastrointestinal Disorders
Another aspect of the present invention is methods for treating or
preventing gastrointestinal disorders in humans or lower animals. Such
methods comprise orally administering by swallowing, to a human or lower
animal in need of such treatment or prevention, a safe and effective
amount of an oral pharmaceutical composition according to the present
invention.
The term "gastrointestinal disorder," as used herein, encompasses any
disease or other disorder of the gastrointestinal tract, preferably the
upper gastrointestinal tract, of a human or lower animal treatable or
preventable by the CBS useful herein. The term "upper gastrointestinal
tract," as used herein, is defined to include the esophagus, the stomach,
the duodenum, and the jejunum. Such upper gastrointestinal tract disorders
include, for example: disorders not manifested by presence of ulcerations
in the gastric mucosa (herein "non-ulcerative gastrointestinal
disorders"), including chronic or atrophic gastritis, non-ulcer dyspepsia,
esophageal reflux disease and gastric motility disorders; and "peptic
ulcer disease," i.e., gastric, duodenal and jejunal ulcers. Included
herein are diseases or disorders caused or mediated by Helicobacter
pylori.
The phrase "safe and effective amount," as used herein, means an amount of
CBS high enough to significantly positively modify the condition to be
treated but low enough to avoid serious side effects (at a reasonable
benefit/risk ratio), within the scope of sound medical judgment. The safe
and effective amount of the oral pharmaceutical composition of the present
invention will vary with the particular condition being treated, the age
and physical condition of the patient being treated, the severity of the
condition, the duration of treatment, the nature of concurrent therapy,
the particular pharmaceutically-acceptable carrier materials utilized, and
like factors within the knowledge and expertise of the attending
physician. The methods of the present invention typically involve
administering from about 100 mg to about 4800 mg of CBS per day, and
preferably from about 200 mg to about 1200 mg per day.
The following examples further describe and demonstrate the present
invention. The examples are given solely for the purpose of illustration,
and are not to be construed as limitations of the present invention since
many variations thereof are possible without departing from its spirit and
scope.
EXAMPLE 1
CBS is prepared according to European Patent 0,075,992 and U.S. Pat. No.
4,801,608 (both incorporated herein by reference in their entirety), and
is used to prepare tablets and capsules as follows.
Uncoated swallowable tablets containing CBS are produced as follows: 100 kg
of CBS is granulated with 23.8 kg of corn starch using 5.85 kg of povidone
K30 dissolved in 51.0 kg of ethanol. The granulate, having a particle size
of less than 1 mm, is blended with 7.8 kg of polacrilin potassium, 1.98 kg
of polyethylene glycol 6000 and 0.66 kg of magnesium stearate, and is
compressed into tablets.
Coated swallowable tablets containing CBS are produced by filmcoating the
above described compressed tablets with about 12 mg hydroxypropyl
methylcellulose and about 2 mg polyethylene glycol per tablet. These
tablets are representative of commercially used De-Nol.RTM. swallowable
tablets.
Reduced density swallowable capsules according to the present invention
(having packing densities of 0.6 g of CBS composition/ml and 0.86 g of CBS
composition/ml) are produced using the granulate for uncoated swallowable
tablets as described above, filled into hard gelatin capsules No. 0, using
a rotary capsule filling machine. The packing density of the capsule
content is adjusted by settings of the piston within the dosator.
The densities of the uncoated and coated tablets and of the contents of the
two different capsules are calculated with respect to the amount of
CBS-containing composition per units of volume. The results are presented
in the following Table 1:
TABLE 1
______________________________________
Packing density
Packing
(CBS-containing
volume composition/volume)
______________________________________
Tablet, uncoated 0.25 ml 1.7 g/ml
Tablet, coated 0.25 ml 1.7 g/ml
Reduced Density Capsule #1
0.70 ml 0.6 g/ml
Reduced Density Capsule #2
0.50 ml 0.86 g/ml
______________________________________
EXAMPLE 2
Bismuth absorption in dogs
Healthy fasted dogs (Beagles) are given a single dose of coated tablets or
the reduced-density capsules #1 of Example 1. The dogs are each dosed with
2 tablets or 2 capsules, giving a total dose of 600 mg CBS per dog. After
ingestion, blood samples are taken at 9 intervals up to 8 hours. The
bismuth content is measured in the blood by atomic absorption.
In dogs the reduced density capsules according to the present invention
give a lower systemic bismuth absorption (for both the "blood Cmax", which
is the maximum bismuth blood level measured at a time after ingestion, and
the "blood AUC", which is the Area Under bismuth concentration-time Curve,
over an 8 hour period after dosing) than does the prior art tablet dosage
form having the same composition but compressed to a higher density.
EXAMPLE 3
Bismuth absorption in humans
Healthy fasted human volunteers are dosed with the uncoated and coated
tablets and the two different capsules of Example 1. The volunteers are
each dosed with 2 tablets or 2 capsules, giving a total dose of 600 mg CBS
per volunteer. After ingestion blood samples are taken at several
intervals up to 3 hours, and the urine is collected for 3 hours. The
bismuth content is measured in the blood plasma and in the urine by atomic
absorption.
In humans the reduced density capsules of the present invention give a much
lower systemic bismuth absorption (for both blood Cmax and blood AUC, as
well as for bismuth in urine) than does the prior art dosage form.
Furthermore, there appears to be a reverse relationship between the
density of the dosage form and the amount of systemic bismuth absorption
therefrom, with compositions of packing density less than about 1 g/ml
having substantially less bismuth absorbed than the prior art tablet
having packing density above 1 g/ml.
Oral administration of the reduced density capsules of the present
invention is very effective for treating patients suffering from ulcers
and/or Helicobacter pylori infection.
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